PROJECT SUMMARY Children and adolescents with glomerular disease have unique and potentially modifiable risk factors for compromised bone health. As delineated by the applicant?s K23 project, glomerular disease is associated with multiple disturbances in vitamin D homeostasis and mineral metabolism, independent of and exacerbated by reduced kidney function. These patients are also exposed to medications which may negatively impact bone health, most notably high-dose and long-term glucocorticoid therapy. With at least 90% of peak bone mass established by 18 years of age, the growing skeleton is particularly vulnerable to such threats to healthy bone accrual which may have a critical impact on lifelong skeletal health. Several studies have demonstrated reduced bone mineral density in children with idiopathic nephrotic syndrome and in young adults with a history of nephrotic syndrome in childhood. However, studies addressing the outcome of fracture or other skeletal complications in children or adults with glomerular disease are lacking. The applicant recently led the development of a multi-institutional Pediatric Glomerular Disease Learning Health System in partnership with the PEDSnet clinical data research network and the NephCure Kidney Network patient-powered research network. The goal of this Learning Health System is to serve as a sustainable resource for the efficient conduct of observational outcomes and comparative effectiveness research, quality improvement, and pragmatic clinical trials in children with glomerular disease. PEDSnet is a consortium of eight academic pediatric health centers that has harmonized their diverse electronic health record (EHR) systems to create a standardized analysis-ready, longitudinal database (2009-2015) with over 4.5 million children. The NephCure Kidney Network is a patient registry designed to sustain a ?research-ready? and engaged patient community. The proposed work will leverage and integrate the complementary infrastructures of these networks. This proposal comprises: 1) the first population-based cohort study of skeletal outcomes (fracture, slipped capital femoral epiphysis, and osteonecrosis) in children and adolescents with glomerular disease in order to identify disease-specific risk factors and compare their rates of fracture to healthy peers, frequency matched on age, sex, race, and center; and 2) the first study to determine the burden of patient-reported musculoskeletal complications in children and young adults with glomerular disease. These studies represent the first use of the Pediatric Glomerular Disease Learning Health System and the NephCure Kidney Network for integrated observational research of EHR-based and patient-reported outcomes and are therefore, fundamental to future observational research activities in these networks. The results will serve specifically to inform the design of pragmatic trials to improve bone health in this patient population.